Under the current award, we have acquired exciting new evidence that satellite cells are necessary for the proper remodeling of the extracellular matrix during hypertrophy. We reported that in muscle depleted of satellite cells there was a significant increase in fibrosis that was associated with a blunted long-term hypertrophic response. Our preliminary data show that activated satellite cells/myogenic progenitor cells (MPCs) are capable of repressing the synthesis of extracellular matrix components by fibroblasts through exosomal delivery of microRNAs. We hypothesize that the loss of satellite cells removes this brake leading to the over-production of collagen and fibrosis, ultimately limiting long-term hypertrophic growth. We further hypothesize that fibrosis as a result of loss of satellite cells preferentially limits growth in fast muscle fibers, whereas growth of slow fibers i limited by myonuclear domain size. Thus, fast fibers display a relatively flexible myonuclear domain, whereas slow fibers may have a more stringent requirement for satellite cells for growth. The objectives of this proposal are to use genetic mouse models and in vitro cell culture to investigate these novel roles for satellite cells in skeletal muscle adaptation by pursuing the following aims. Aim 1 will determine the mechanisms underlying satellite cell regulation of extracellular matrix remodeling during skeletal muscle hypertrophy. Aim 2 will determine if fibrosis attenuates long-term hypertrophy in satellite cell-depleted muscle, and the influence of fiber type composition. Aim 3 will determine if there is a fiber type-specific requirement for satellite cell fusion during skeletal muscle hypertrophy. Our published work and new preliminary data clearly show that our understanding of satellite cell function in adult skeletal muscle adaptation remains incomplete. The studies described in this proposal address this fundamental gap in our knowledge and are expected to provide critical information necessary to more effectively evaluate the use of satellite cells as a therapeutic agent to prevent or restore the los of skeletal muscle mass associated with dystrophies, cancer, age and rehabilitation following disuse.